Abstract

Objective: To determine if circulating metabolic intermediates are related to insulin resistance and beta-cell dysfunction in persons at risk for type 2 diabetes.

Methods: In 73 sedentary, overweight to obese, dyslipidemic individuals, insulin action was derived from a frequently sampled intravenous glucose tolerance test. Plasma concentrations of 75 amino acids, acylcarnitines, free fatty acids and conventional metabolites were measured with a targeted, mass-spectrometry-based platform. Principal components analysis followed by backward stepwise linear regression was used to explore relationships between measures of insulin action and metabolic intermediates.

Results: The 75 metabolic intermediates clustered into 19 factors comprised of biologically related intermediates. A factor containing large neutral amino acids was inversely related to insulin sensitivity (S_I; R²=0.26). A factor containing fatty acids was inversely related to the acute insulin response to glucose (R²=0.12). Both of these factors, age, and a factor containing medium-chain acylcarnitines and glucose were inversely and independently related to the disposition index (DI; R²=0.39). Gender differences were found for metabolic predictors of S_I and DI.

Conclusions: In addition to well-recognized risks for insulin resistance, elevated concentrations of large, neutral amino acids independently associated with insulin resistance. Fatty acids were inversely related to pancreatic response to glucose. Both large neutral amino acids and fatty acids were related to an appropriate pancreatic response, suggesting that these metabolic intermediates might play at role in the progression to type 2 diabetes, one by contributing to insulin resistance and the other to pancreatic failure. These intermediates might exert gender-specific effects on insulin action.